GEO series
Distinct transcriptional and functional modules mediate resistance to targeted therapy in glioblastoma
GSE319338
Homo sapiens; Mus musculus
Expression profiling by high throughput sequencing
13 samples
Submitted 2026/07/27
Platform GPL34328Platform GPL34281
Summary
Glioblastomas (GBM) harbor recurrent mutations in receptor tyrosine kinase (RTK) signaling, yet targeted therapy has shown limited efficacy. To dissect mechanisms underlying drug resistance, we combined single cell RNA-sequencing (scRNA-seq) and functional genomic screens following MEK or SHP2 inhibition in preclinical GBM models. ScRNA-seq of mouse intracranial xenografts revealed that although mesenchymal-like GBM subpopulation exhibits heightened sensitivity to both MEK or SHP2 inhibition, each targeted therapy induces distinct transcriptional signatures. Genome-wide CRISPR interference (CRISPRi) screens identified shared mediators of MEK or SHP2 inhibitor sensitivity enriched for the conserved downstream effector Ras/RAF/MEK pathway. However, genes uniquely mediating SHP2 inhibitor response were enriched for Ras/RAF/MEK-independent signaling modules such as SRC family kinases, GSK3B, and SMAD proteins regulating cell adhesion and differentiation. Perturb-seq of 39 target genes following MEK or SHP2 inhibition identified 10 discrete clusters with distinct effects on Ras signaling and cellular phenotypes. Proliferation and differentiation gene expression signatures clustered genetic perturbations into 4 broad classes: cell cycle regulators, positive effectors of Ras/RAF/MEK signaling, negative regulators of Ras/RAF/MEK signaling, or parallel regulators of Ras/RAF/MEK independent pathways. Combinatorial linear modeling from transcriptional signatures identified multiple gene-drug relationships including expected synergistic and potentiation combinations between MEK, SHP2, and CDKN2A/B and unexpected antagonistic and neomorphic interactions with indirect effectors such as LZTR1 and RAC1. Finally, preclinical testing of predicted synergistic inhibitor combinations with MEK, SHP2, and CDK4/6 inhibition demonstrated improved efficacy compared to molecular monotherapy in multiple GBM preclinical models. Taken together, our approach provides a systems-level framework for understanding RTK-Ras signaling network principles and targeted therapy resistance in glioblastoma.
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE319338_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 13 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1423048. Searching any of these in the dataset finder brings you back here.
Study design
4 × Perturb-seq in SB28 cells treated with vehicle/selumetinib/RMC-4550, 10x vs 3 × GBM43 intracranial xenografts, vehicle control, sample vs 3 × GBM43 intracranial xenografts, selumetinib treated, sample vs 3 × GBM43 intracranial xenografts, RMC-4550 treated, sample
Supports a case/control comparison: 6 samples read as cases, 3 as controls.
4 replicated groups read from 13 sample titles; they account for 13 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM9515822 Perturb-seq in SB28 cells treated with vehicle/selumetinib/RMC-4550, 10x lane 1
- GSM9515823 Perturb-seq in SB28 cells treated with vehicle/selumetinib/RMC-4550, 10x lane 2
- GSM9515824 Perturb-seq in SB28 cells treated with vehicle/selumetinib/RMC-4550, 10x lane 3
- GSM9515825 Perturb-seq in SB28 cells treated with vehicle/selumetinib/RMC-4550, 10x lane 4
- GSM9515826 GBM43 intracranial xenografts, vehicle control, sample 1
- GSM9515827 GBM43 intracranial xenografts, vehicle control, sample 2
- GSM9515828 GBM43 intracranial xenografts, vehicle control, sample 3
- GSM9515829 GBM43 intracranial xenografts, selumetinib treated, sample 1
- GSM9515830 GBM43 intracranial xenografts, selumetinib treated, sample 2
- GSM9515831 GBM43 intracranial xenografts, selumetinib treated, sample 3
- GSM9515832 GBM43 intracranial xenografts, RMC-4550 treated, sample 1
- GSM9515833 GBM43 intracranial xenografts, RMC-4550 treated, sample 2
- GSM9515834 GBM43 intracranial xenografts, RMC-4550 treated, sample 3
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